Radio-labeled compositions are important tools in medical diagnosis and treatment. Such compositions may be employed in a variety of techniques, including the diagnosis of deep venous thrombi, the study of lymph node pathology, and the detection, staging and treatment of neoplasms. When employing radio-labeled compositions for in vivo diagnostic or therapeutic applications, it is important that the radionuclide preferentially localize in target tissues. Therefore, radionuclides are generally coupled to targeting agents to provide preferential binding to or absorption by the particular cells or tissue(s) of interest. Radionuclides are typically bound to a chelating agent, and the chelating agent is coupled to a targeting moiety to provide a radio-labeled composition capable of binding selectively to a specified population of target cells or tissue(s).
Radionuclides such as .sup.99m Tc, .sup.131 I, .sup.123 I, .sup.117m Sn, .sup.111 In, .sup.113 In, .sup.97 Ru, .sup.76 Br, .sup.77 Br, .sup.203 Pb, .sup.18 F, .sup.67 Ga, .sup.89 Zr, and .sup.64 Cu have been proposed for use as diagnostic imaging agents. .sup.99m Tc is one particularly promising diagnostic imaging agent. Technetium-99m is produced commercially in generators by eluting a saline solution through a matrix containing molybdenum. The metastable technetium isotope in such eluates is found in the chemically stable, oxidized pertechnetate form .sup.99m TcO.sub.4.sup.-. Because pertechnetate-.sup.99m Tc has a valence state of +7, it will not complex with the most commonly used carriers for radionuclide tissue imaging. .sup.99m TcO.sub.4.sup.- is therefore commonly reduced to lower oxidation states, such as .sup.99m TcO.sup.3+ and .sup.99m TcO.sub.2.sup.+ by admixing .sup.99m TcO.sub.4.sup.- isotonic saline solutions with technetium reductants such as stannous, ferrous and chromous salts and acids such as sulfuric and hydrochloric.
Therapeutic radionuclides such as .sup.32 P and .sup.131 I have been used to treat malignancies such as polycythemia vera and metastatic thyroid carcinoma, respectively. A variety of radionuclides may be useful for therapeutic applications, including alpha emitters, low, medium and high range beta emitters, and radionuclides which act through electron capture and/or internal conversion (auger electrons). Sources of alpha emitters, such as .sup.211 At, are relatively limited, while beta sources are far more plentiful. Numerous medium range beta sources, including .sup.47 Sc, .sup.67 Cu, .sup.131 I, .sup.153 Sm, .sup.109 Pd, .sup.105 Rh, and .sup.186 Re, have been proposed for therapeutic applications. .sup.131 I is frequently used for antibody-directed therapy, but it suffers from increased non-target toxicity due to the abundance of high energy gamma rays emitted therefrom and dehalogenation. Concerns related to dehalogenation of .sup.131 I therapeutic compositions may be substantially reduced by attachment of para-iodophenyl moieties as taught in European Patent Application Publication 0 203 764. Long range beta particle sources potentially suitable for therapeutic administration include .sup.32 P, .sup.90 Y and .sup.188 Re. .sup.186 Re and .sup.188 Re also emit gamma radiation at essentially the same energy as the gamma emission of .sup.99m Tc, which allows the biodistribution of rhenium radiopharmaceuticals to be readily monitored using conventional gamma camera instrumentation.
Therapeutic compositions comprising beta emitting radionuclides may undergo radiolysis during preparation and/or in vitro storage. During radiolysis, emissions from the radionuclide attack other constituents of the complex or compound, or other compounds in proximity, which results in inter- and intra-molecular decomposition. Radiolytic decay poses serious safety concerns, since decomposition or destruction of the radionuclide chelate, the radionuclide chelate-targeting agent linkage, or the specificity conferring portion of the targeting agent results in non-targeted radioactivity. Radioactivity which is not linked to a functional targeting agent will accumulate in non-target tissues, and decomposition of the radionuclide composition prior to or during administration dramatically decreases the targeting potential and thus increases the toxicity of the therapeutic radionuclide composition. It is thus important, particularly with respect to therapeutic radionuclide preparations intended for in vivo administration, to ensure that the radioactive moiety is stably linked to the targeting moiety, and the specificity of the targeting agent is preserved.
.sup.99m Tc and radioactive rhenium, including .sup.186 Re and .sup.188 Re, are Group VIIA congeners. Rhenium and technetium share many physical properties, such as size, shape, dipole moment, formal charge, ionic mobility, lipophilicity, and the like. For example, many chelating agents which have been developed and/or used for .sup.99m Tc are also suitable for use with rhenium radionuclides. Little is known, however, about the properties of radioactive rhenium therapeutic compositions, since research involving rhenium radionuclides is still at a relatively preliminary stage. Perrhenate (ReO.sub.4.sup.-), which is formed as a result of unstable rhenium complexes in lower oxidation states moving to higher oxidation states, is the primary decomposition product of rhenium radionuclide compositions.
E. Deutsch, et al., in an article entitled "The Chemistry of Rhenium and Technetium as Related to the Use of Isotopes of these Elements in Therapeutic and Diagnostic Nuclear Medicine", Nucl. Med. Biol., Vol 13, No. 4, pp. 465-477, 1986, present a review of the comparative properties of technetium and rhenium radionuclides and their applications to therapeutic and diagnostic nuclear medicine. Technetium and rhenium both exhibit redox chemistry, and pertechnetate and perrhenate, respectively, must be converted to lower oxidation states prior to chemical reaction with chelating agents. The chemistry of rhenium is sufficiently different from that of technetium, however, that the development of rhenium radiopharmaceuticals often cannot be predicated on the known chemistry and biological behavior of .sup.99m Tc radiopharmaceuticals. The most relevant of the chemical differences may be that rhenium complexes are thermodynamically more stable in their higher oxidation states, in the form of perrhenate, than are their technetium analogs. Rhenium compositions are therefore more difficult to reduce than their technetium analogs, and reduced rhenium radiopharmaceuticals tend to be re-oxidized back to perrhenate more readily than analogous technetium radiopharmaceuticals are re-oxidized back to pertechnetate.
Deutsch et al. prepared rhenium radionuclide analogs of .sup.99m Tc bone-seeking radiopharmaceuticals, including .sup.186 Re(Sn)-HEDP [HEDP=(1-hydroxyethylidene)diphosphonate], and [.sup.186 Re(DMPE).sub.3 ].sup.+, [DMPE=1,2-bis(dimethylphosphino)ethane]. In these conjugates, the radionuclide is coupled directly to the inorganic diphosphonate targeting agent. The researchers compared the properties of rhenium preparations, and their in vivo biodistribution, with the corresponding .sup.99m Tc analogs. Decomposition of the rhenium complexes to perrhenate was much more pervasive than decomposition of the technetium analogs to pertechnetate. The presence of perrhenate was attributed to incomplete reduction of perrhenate in the original synthesis, reoxidation of rhenium complexes to perrhenate by adventitious oxygen, and disproportionation of the rhenium radionuclide complex. Deutsch et al. found that chromatographic purification of the rhenium radionuclide preparations was essential to provide satisfactory purity levels. Ascorbic acid was suggested for use as an antioxidant, but the purified preparation still required anaerobic handling and was used as quickly as possible after it was generated. Deutsch et al. concluded that the successful development of a .sup.186 Re(Sn)-HEDP radiopharmaceutical for the palliative treatment of metastatic cancer to bone analogous to the .sup.99m Tc(Sn)-HEDP radiopharmaceutical used to diagnose metastatic bone cancer depends upon the ability to control the redox properties of rhenium radionuclides.
Stabilization of therapeutic radionuclide compositions is a recurrent challenge in the field of therapeutic radionuclide conjugates. Stabilization of radioactive compositions is generally more difficult to achieve without loss of desired properties than stabilization of other, structurally similar chemical compositions. Therapeutic radionuclide compositions behave differently from and are generally less stable than diagnostic radionuclide compositions.
Since decomposition of therapeutic radionuclide compositions is generally so rapid over time, clinical radionuclide preparations are prepared immediately prior to administration. This requires that the treating facility have the laboratory facilities and skilled technicians necessary for manipulating radioactive materials, which generally involves chelating the radionuclide and conjugating the radionuclide to the targeting moiety. Additionally, significant resources are devoted to preparing patients so they may undergo treatment immediately after purification of the therapeutic radionuclide composition. If the preparation is contaminated or does not meet the purity requirements, the patient must either wait a considerable time period for a second preparation, or undergo the trauma of waiting yet a longer interim period. Such delays are traumatic to the patient and waste valuable facility and personnel resources. Effective in vitro stabilization of therapeutic radionuclide compositions would permit more centralized, controlled preparation of therapeutic radionuclide compositions, and thereby provide greater access to therapeutic compositions having higher purity levels.